Browsing by Subject "Transglutaminases"

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    Mechanism of tissue transglutaminase upregulation and its role in ovarian cancer metastasis
    (2012-04) Cao, Liyun; Matei, Daniela; Chan, Rebecca J.; Harrington, Maureen A.; Nakshatri, Harikrishna
    Ovarian cancer (OC) is a lethal disease due to metastasis and chemoresistance. Our laboratory previously reported that tissue transglutaminase (TG2) is overexpressed in OC and enhances OC peritoneal metastasis. TG2 is a multifunctional protein which catalyzes Ca2+-dependent cross-linking of proteins. The purpose of this study was to explore the mechanism by which TG2 is upregulated in OC and its role in OC progression. We demonstrated that transforming growth factor (TGF)-β1 is secreted in the OC milieu and regulates the expression and function of TG2 primarily through the canonical Smad signaling pathway. Increased TG2 expression level correlates with a mesenchymal phenotype of OC cells, suggesting that TGF-β1 induced TG2 promotes epithelial-to-mesenchymal transition (EMT). TG2 induces EMT by negatively regulating E-cadherin expression. TG2 modulates E-cadherin transcriptional suppressor Zeb1 expression by activating NF-κB complex, which leads to increased cell invasiveness in vitro and tumor metastasis in vivo. The N-terminal fibronectin (FN) binding domain of TG2 (tTG 1-140), lacking both enzymatic and GTPase function, induced EMT in OC cells, suggesting the interaction with FN involved in EMT induction. A TGF-β receptor kinase inhibitor, SD-208, blocked TGF-β1 induced TG2 upregulation and EMT in vitro and tumor dissemination in vivo, which confirms the link between TGF-β1 and TG2 in EMT and tumor metastasis. TG2 expression was correlated with the number and size of self-renewing spheroids, the percentage of CD44+CD117+ ovarian cancer stem cells (CSCs) and with the expression level of stem cell specific transcriptional factors Nanog, Oct3/4, and Sox2. These data suggest that TG2 is an important player in the homeostasis of ovarian CSCs, which are critical for OC peritoneal metastasis and chemoresistance. TG2 expression was also increased in CSCs isolated from human ovarian tumors, confirming the implication of TG2 in CSCs homeostasis. Further, we demonstrated that TG2 protects OC cells from cisplatin-induced apoptosis by regulating NF-κB activity. We proposed a model whereby TGF-β-inducible TG2 modulates EMT, metastasis, CSC homeostasis and chemoresistance in OC. These findings contribute to a better understanding of the mechanisms of OC metastasis modulated by TG2.
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    Tissue Transglutaminase Activates Cancer-Associated Fibroblasts and Contributes to Gemcitabine Resistance in Pancreatic Cancer
    (Elsevier, 2016-11) Lee, Jiyoon; Yakubov, Bakhtiyor; Ivan, Cristina; Jones, David R.; Caperell-Grant, Andrea; Fishel, Melissa; Cardenas, Horacio; Matei, Daniela; Department of Otolaryngology--Head & Neck Surgery, School of Medicine
    Resistance to chemotherapy is a hallmark of pancreatic ductal adenocarcinoma (PDA) and has been partly attributed to the dense desmoplastic stroma, which forms a protective niche for cancer cells. Tissue transglutaminase (TG2), a Ca(2+)-dependent enzyme, is secreted by PDA cells and cross-links proteins in the tumor microenvironment (TME) through acyl-transfer between glutamine and lysine residues, promoting PDA growth. The objective of the current study was to determine whether secreted TG2 by PDA cells alters the response of pancreatic tumors to gemcitabine. Orthotopic pancreatic xenografts and co-culture of PDA and stromal cells were employed to determine the mechanisms by which TG2 alters tumor-stroma interactions and response to gemcitabine. Analysis of the pancreatic The Cancer Genome Atlas (TCGA) database demonstrated that increased TG2 expression levels correlate with worse overall survival (hazard ratio=1.37). Stable TG2 knockdown in PDA cells led to decreased size of pancreatic xenografts and increased sensitivity to gemcitabine in vivo. However, TG2 downregulation did not increase cytotoxicity of gemcitabine in vitro. Additionally, multivessel density and gemcitabine uptake in pancreatic tumor tissue, as measured by mass spectrometry (MS-HPLC), were not significantly different in tumors expressing TG2 versus tumors in which TG2 was knocked down. Fibroblasts, stimulated by TG2 secreted by PDA cells, secrete laminin A1, which protects cancer cells from gemcitabine-induced cytotoxicity. In all, our results demonstrate that TG2 secreted in the pancreatic TME orchestrates the cross talk between cancer cells and stroma, impacting tumor growth and response to chemotherapy. Our study supports TG2 inhibition to increase the antitumor effects of gemcitabine in PDA.